The Tabas laboratory utilizes cell-culture models and induced mutant mice to explore areas of macrophage cellular and molecular biology that are pertinent to the development of atherosclerosis. A major focus of the laboratory is the molecular and cellular mechanisms and consequences resulting from macrophage apoptosis and from the phagocytic clearance of apoptotic cells, particularly in advanced atherosclerotic lesions. We have elucidated a multi-hit model of macrophage apoptosis that involves an ER stress pathway known as the Unfolded Protein Response (UPR). The key distal UPR effector responsible for cholesterol-induced macrophage death is the molecule CHOP (GADD153). CHOP enables apoptosis by promoting calcium release from the ER, which in turn induces a number of downstream apoptotic pathways through activation of calcium/calmodulin-dependent protein kinase II (CaMKII), STAT1, and NADPH oxidase. However, apoptosis requires a "second hit," and we have evidence that engagement of macrophage pattern recognition receptors (PRRs), notably toll-like receptors and scavenger receptors, play an important role in this regard. PRR engagement triggers apoptosis in ER-stressed macrophages by further promoting apoptotic signaling and suppressing compensatory cell survival signaling. We have developed a number of genetically altered mouse models to test these ideas in vivo. For example, deficiencies of CHOP, STAT1, or both SRA and CD36 (scavenger receptors) decrease advanced lesional macrophage apoptosis and plaque necrosis in Apoe-/- and/or Ldlr-/- mice. Moreover, in collaboration with Drs. Domenico Accili and Alan Tall at Columbia, we have shown the relevance of this overall pathway of macrophage apoptosis to advanced atherosclerosis in insulin resistant-states. Finally, the laboratory has in-vitro mechanistic studies and in-vivo mouse studies to explore the critical role of apoptotic cell clearance ("efferocytosis"), which we feel is a major determinant of whether macrophage death leads to the beneficial consequence of decreased cellularity or to the detrimental plaque-disrupting consequence of lesional necrosis. We discovered that a receptor called Mertk plays a critical role in the efferocytosis of apoptotic macrophages both in vitro and in advanced atherosclerotic lesions. The future goals of the laboratory are to pursue each of the areas in more depth both mechanistically and physiologically and to continually pinpoint areas of therapeutic potential, particularly in preventing the conversion of benign atherosclerotic lesions into disease-causing vulnerable plaques.
Moore, K.J. and Tabas, I. (2011)
Macrophages in the pathogenesis of atherosclerosis. Cell 145:341-355.Tabas, I.
and Ron, D. (2011)
Molecular mechanisms integrating pathways of endoplasmic reticulum stress-induced apoptosis. Nature Cell Biology 13:184-190.
Seimon, T.A., Liao, X., Magallon, J, Nguyen, M., Witztum, J.L., Tsimikas, S., Moore, K.J., Golenbock, D., and Tabas, I. (2010)
Atherosclerosis-relevant CD36 ligands trigger Toll-like receptor 2-dependent apoptosis in macrophages undergoing endoplasmic reticulum stress. Cell Metabolism 12:467-482. PMCID: PMC2991104Tabas. I. (2010)
Macrophage death and defective inflammation resolution in atherosclerosis. Nature Immunol. Reviews. 10:36-46. PMCID: PMC2854623
Seimon, T., Wang, Y., Kuriakose, G., Han, S., Senokuchi, T., Tall, A., Tabas, I. (2009)
Deficiency of p38α in macrophages promotes apoptosis and plaque necrosis in advanced murine atherosclerotic lesions. J. Clin. Invest. 119:886-898.
Thorp, E., Li, G., Seimon, T.A., Kuriakose, G., Ron, D., Tabas, I. (2009)
Reduced apoptosis and plaque necrosis in advanced atherosclerotic lesions of Apoe-/- and Ldlr-/- mice lacking CHOP. Cell Metabolism, 9:474-481.
Timmins, J., Ozcan, L., Seimon, T.A., Li, G., Malagelada, C., Backs, J., Backs, T., Bassel-Duby, R., Olson, E.N., Anderson, M.E., and Tabas, I. (2009)
Calcium/calmodulin-dependent protein kinase II links endoplasmic reticulum stress with Fas and mitochondrial apoptosis pathways. J. Clin. Invest. In press.
Woo, C.W., Cui, D., Arrelano, J., Dorweiler,B., Harding, H., Fitzgerald, K.A., Ron, D., and Tabas, I. (2009)
Adaptive suppression of the ATF4-CHOP branch of the unfolded protein response by toll-like receptor signaling. Nature Cell Biol. In press.
Li, G., Mongillo, M., Chin, K-T., Harding, H., Ron, D., Marks, A.R., and Tabas, I. (2009)
Role of ERO1α-mediated stimulation of inositol 1,4,5-triphosphate receptor activity in endoplasmic reticulum stress-induced apoptosis. In revision for J. Cell Biol.
Thorp, E., Cui, D., Kuriakose, G., and Tabas, I. (2008)
Mutation of the Mertk receptor promotes apoptotic cell accumulation and plaque necrosis in advanced atherosclerotic lesions of apolipoprotein E-deficient mice. Arterio. Thromb. Vasc. Biol. 28:1421-8.
Thorp, E., Li, Y., Bao, L., Yao, P.M., Kuriakose, G., Rong, J., Fisher, E.A., Tabas, I. (2008)
Increased apoptosis in advanced atherosclerotic lesions of Apoe-/- mice lacking macrophage Bcl-2. Arterio. Thromb. Vasc. Biol. 29:169-72.
Li, Y., Zhang, Y., Dorweiler, B., Cui, D., Wang, T., Woo, C.W., Wolberger, C., Imai, S., Tabas, I. (2008)
Extracellular Nampt protects macrophages from ER stress-induced apoptosis via a non-enzymatic interleukin-6/STAT3 signaling mechanism. J. Biol. Chem. 283:34833 - 34843.
Cui, D., Thorp, E., Li, Y., Wang, N., Yvan-Charvet, L., Tall, A.R., Tabas, I. (2007)
Pivotal Advance: Macrophages become resistant to cholesterol-induced death after phagocytosis of apoptotic cells. J. Leukoc. Biol. 82:1040-50.
Seimon, T.A., Obstfeld, A., Moore, K.J., Golenbock, D.T., and Tabas, I. (2006)
Combinatorial pattern recognition receptor signaling alters the balance of life and death in macrophages. Proc. Natl. Acad. Sci. U.S.A. 103:19794-19799.